The advantages of sustained release products are widely recognized in the art and are of extreme importance in the pharmaceutical field. Through the use of such products, orally administered medications can be delivered continuously at a uniform rate over a prolonged period of time so as to provide a stable, predetermined concentration of a drug in the bloodstream, without requiring close monitoring and frequent re-administration.
The sustained release character of such products is achieved by one of two methods: 1) providing a sustained release coating upon tablets or microspheres wherein slow release of the active occurs via either gradual permeation through or gradual breakdown of this coating or 2) providing a sustained release matrix, such as a fat, a wax, or a polymeric material intermixed with the active ingredient in the tablet itself. See, e.g., Manford Robinson, "Sustained Action Dosage Forms" in The Theory and Practice of Industrial Pharmacy, ch. 14 (L. Lachman et al., eds., 2d ed., 1976).
Such sustained release matrix formulations are typically prepared by methods involving pre-granulating the active ingredient together with the matrix material via a wet granulation, solvent granulation, shear-melt or roto-melt granulation, or a wet pre-adsorption technique. In these techniques, a liquid phase is used in order to uniformly mix and/or closely contact the ingredients together so as to provide an evenly distributed matrix in intimate association with the active ingredient. These formation processes help prevent creation of interspersed quick-release zones which would result in discontinuous dissolution of the tablet and thus cause bioconcentration spikes of active ingredient in the patient. They frequently also result in tablets of a relatively higher density than the dry mixed ones, thus allowing the use of tablets, for a given dose, that are smaller than those made by dry mixing for the same intended release rate.
However, these liquid phase methods require a multiplicity of steps and equipment for storage, handling, and dispensing of liquids, for drying, and/or for heating of the ingredients. When the liquid is water, its volume must be very carefully controlled so as to prevent any disintegrant in the formula from swelling. Also, water is incompatible with hygroscopic active ingredients. Yet, when the liquid is instead a volatile organic solvent, additional precautions must be taken to address the risks of fire, explosion, and worker exposure. Where a melt processing technique is used, heating presents a risk of inactivation of at least some of the active material and is incompatible for use with some active ingredients.
Thus, dry mixing has sometimes been used to form sustained release matrix tablets. This technique involves pre-mixing the matrix material with the active ingredient, without the use of added liquids or heat, so that only ambient humidity, temperature, and particle-to-particle surface interactions and/or static electrical attraction foster adherence, if any, of the ingredients to one another.
For example, U.S. Pat. No. 4,259,314 to Lowey employs a mixture of cellulose ethers--hydroxypropylmethylcellulose ("HPMC") and hydroxypropyl cellulose--to form a sustained release matrix in which the cellulose ether mixture has a weighted average viscosity rating of 250-4500 cps, and preferably 1200-2900 cps. These are equilibrated under an atmosphere having up to 40% relative humidity and then pre-mixed together before drying to a moisture content of 1% or less. The active and other remaining ingredients (after they have equilibrated under .ltoreq.40% humidity) are combined with the cellulose ether mixture and the resulting combination is compressed at .ltoreq.40% humidity to produce a tablet.
U.S. Pat. No. 5,451,409 to Rencher et al. discloses a dry mixed pseudoephedrine tablet in which a mixture of hydroxypropyl cellulose and hydroxyethyl cellulose forms the sustained release matrix; 0.5-10% HPMC is also added as a binder.
U.S. Pat. No. 5,085,865 to Nayak discloses a two-layer tablet wherein one layer, which may be formed using a dry mixing process, comprises a 60 mg pseudoephedrine controlled release matrix formulation. The matrix or "sustained release agent" comprises cellulose ethers--hydroxypropyl and/or hydroxyethyl cellulose--and, preferably also, sodium croscarmelose; this agent is present in an amount equivalent to at least twice that of pseudoephedrine. Up to half of the cellulose ether component may consist of HPMC.